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PubMed2026

Systemic immune activation in hereditary cancer predisposition syndromes: a cross-sectional study.

BACKGROUND: Immune surveillance mechanisms contribute to the elimination of precancerous lesions in hereditary cancer predisposition syndromes (HCPSs). METHODS: By combining single-cell transcriptomics, multiparametric mass cytometry and cytokine profiling of the systemic immune environment in 391 individuals among whom 227 are living with HCPSs we investigated phenotypic alterations in cancer-free individuals with HCPS. RESULTS: A decrease in peripheral B cell abundance and their more differentiated phenotype have been confirmed both in breast cancer patients with germline pathogenic variants in BRCA1 (gpath(BRCA1)) and in patients living with Lynch syndrome (LS). Pre-cancer women with gpath(BRCA1) exhibited an activated phenotype of multiple immune cell lineages, similar to those with manifest disease. In LS, B cell phenotypes exhibited the largest changes in response to cancer eradication, while increased peripheral IL-6 levels was detected even in presymptomatic individuals with LS. CONCLUSIONS: HCPS-specific differences in the phenotype of the systemic immune system might be leveraged in future risk-reducing strategies.

Humans↗

PubMed2003

Interplay of transcriptomics and proteomics.

Despite the obvious attractions of parallel profiling of transcripts and proteins on a global 'omic' scale, there are practical and biological differences involved in their application. Transcriptomics is now a robust, high-throughput, cost-effective technology capable of simultaneously quantifying tens of thousands of defined mRNA species in a miniaturized, automated format. Conversely, proteomic analysis is currently much more limited in breadth and depth of coverage owing to variations in protein abundance, hydrophobicity, stability, size and charge. Nevertheless, transcriptomic and proteomic data can be compared and contrasted provided the studies are carefully designed and interpreted. Differential splicing, post-translational modifications and data integration are among some of the future challenges to tackle.

Biotechnology↗

PubMed2006

The functional characterization of normal and neoplastic human enterochromaffin cells.

CONTEXT: Neuroendocrine regulation of small intestinal (SI) function is poorly understood because pure neuroendocrine cells are unavailable, whereas the biological basis of SI carcinoid tumors is unknown because neoplastic human enterochromaffin (EC) cells are unavailable. OBJECTIVE: The objective of this study was to define the secretory regulation and transcriptome of naive and neoplastic SI neuroendocrine cells. DESIGN: EC cells from human ilea were isolated and purified, and a malignant EC cell carcinoid cell line (KRJ-I) was characterized. METHODS: Human ilea from right hemicolectomies were pronase/collagenase digested and Nycodenz gradient centrifuged, and EC cells were fluorescence-activated cell sorting (FACS) sorted after acridine orange labeling. Enrichment was defined by immunostaining, gene expression, serotonin (5-HT) content, and real-time RT-PCR. Naive FACS-sorted EC and KRJ-I cells were cultured, and 5-HT secretion was measured after stimulation with forskolin, isoproterenol, acetylcholine, gamma-aminobutyric acid A (GABA(A)), pituitary adenylate cyclase-activating polypeptide (PACAP)-38, and gastrin. Normal and neoplastic EC cell transcriptomes were acquired by Affymetrix profiling (U133A). RESULTS: FACS produced 100 +/- 0.3% (chromogranin A staining) and 99 +/- 0.7% pure EC cells by immunostaining for tryptophan hydroxylase with greater than 67-fold enrichment and a 5-HT content of 180 +/- 18 ng/mg protein (mucosa, 3.5 +/- 0.9). Forskolin- and isoproterenol-stimulated 5-HT secretion was 10-100 times more potent for naive cells (EC(50), 1.8 x 10(-9) m; 5.1 x 10(-9) m) than neoplastic cells (EC(50), 2.1 x 10(-7) m; 8.1 x 10(-8) m), but the effect of PACAP-38 was similar (EC(50), 1 x 10(-7) m). Isoproterenol stimulated cAMP levels 1.6 +/- 0.1-fold vs. basal (EC(50), 2.7 x 10(-9) m). Acetylcholine inhibited naive EC cell 5-HT secretion more potently than neoplastic (IC(50), 3.2 x 10(-9) vs. 1.6 x 10(-7) m), whereas GABA(A) was more potent in neoplastic cells (IC(50), 3.9 x 10(-10) vs. 4.4 x 10(-9) m). Octreotide inhibited naive, but not neoplastic, basal 5-HT secretion. Gastrin had no effect on 5-HT secretion. Comparison of naive and neoplastic transcriptomes revealed shared neuroendocrine and EC cell-specific marker genes. Real-time PCR confirmed that expression of adrenergic (beta1), somatostatinergic (SST(R)2), and neural (VPAC(1) and GABA(A)) receptors occurred on both cell types, but PACAP type 1 (PAC(1)) and cholecystokinin type 2 (CCK(2)) were undetectable. The putative carcinoid malignancy genes (MTA1 and MAGE-D2) were unique to the neoplastic EC cell transcriptome. CONCLUSION: These data support novel methodology to purify live human EC cells for functional characterization and transcriptome assessment, which will allow identification of new targets to control the secretion and proliferation of SI carcinoids.

Carcinoid Tumor↗

PubMed2026

Profiler: an open web platform for multi-omics analysis.

MOTIVATION: High-throughput multi-omics technologies produce increasingly large and heterogeneous datasets that are difficult to analyze without advanced computational expertise. Existing bioinformatics tools are often fragmented or limited to specific omics types, hindering reproducibility and accessibility. There is a critical need for an integrated, user-friendly, and scalable platform capable of supporting multi-omics analyses across different data modalities. RESULTS: We present Profiler, an open-source, modular platform that unifies data import, quality control, preprocessing, statistical testing, machine and deep learning, biomarker discovery, pathway and drug-target enrichment, and survival modeling within a single reproducible environment. Built in Python with Streamlit, Profiler is available as both a web-based platform deployed on high-performance computing and a desktop version for local execution, enabling flexible usage across computational infrastructures. Profiler supports diverse omics modalities, including proteomics, transcriptomics, lipidomics, and electroencephalogram data. Through applications to glioblastoma proteomic, pancancer, and multi-omics datasets, Profiler reproduced known molecular subtypes, revealed potential therapeutic targets, and generated fully traceable analysis reports within minutes. By integrating advanced analytics behind an intuitive interface, Profiler democratizes multi-omics analysis and provides a robust, scalable foundation for systems biology and precision medicine research. AVAILABILITY AND IMPLEMENTATION: Profiler is open-source and freely available via its web platform (https://prism-profiler.univ-lille.fr) and GitHub (web version: https://github.com/yanisZirem/Profiler_v1_requests_datatests, desktop version: https://github.com/yanisZirem/prism-profiler), and archived on Zenodo (DOI: https://doi.org/10.5281/zenodo.17478158).

Software↗

PubMed2024

Integration of Imaging-based and Sequencing-based Spatial Omics Mapping on the Same Tissue Section via DBiTplus.

Spatially mapping the transcriptome and proteome in the same tissue section can significantly advance our understanding of heterogeneous cellular processes and connect cell type to function. Here, we present Deterministic Barcoding in Tissue sequencing plus (DBiTplus), an integrative multi-modality spatial omics approach that combines sequencing-based spatial transcriptomics and image-based spatial protein profiling on the same tissue section to enable both single-cell resolution cell typing and genome-scale interrogation of biological pathways. DBiTplus begins with in situ reverse transcription for cDNA synthesis, microfluidic delivery of DNA oligos for spatial barcoding, retrieval of barcoded cDNA using RNaseH, an enzyme that selectively degrades RNA in an RNA-DNA hybrid, preserving the intact tissue section for high-plex protein imaging with CODEX. We developed computational pipelines to register data from two distinct modalities. Performing both DBiT-seq and CODEX on the same tissue slide enables accurate cell typing in each spatial transcriptome spot and subsequently image-guided decomposition to generate single-cell resolved spatial transcriptome atlases. DBiTplus was applied to mouse embryos with limited protein markers but still demonstrated excellent integration for single-cell transcriptome decomposition, to normal human lymph nodes with high-plex protein profiling to yield a single-cell spatial transcriptome map, and to human lymphoma FFPE tissue to explore the mechanisms of lymphomagenesis and progression. DBiTplusCODEX is a unified workflow including integrative experimental procedure and computational innovation for spatially resolved single-cell atlasing and exploration of biological pathways cell-by-cell at genome-scale.

Journal Article↗

PubMed2024

Integration of Imaging-based and Sequencing-based Spatial Omics Mapping on the Same Tissue Section via DBiTplus.

Journal Article↗

PubMedDate not supplied

Micro serial analysis of gene expression in normal human choroid and retinal pigment epithelial transcriptomes.

PURPOSE: To investigate the gene expression profile of the normal human choroid/retinal pigment epithelium(RPE) tissues. METHODS: Micro serial analysis of gene expression (Micro SAGE) was performed. A SAGE library was constructed from 110 microg of total RNA of normal human choroid/RPE tissue, and cloned tag concatemers transformed to E.coli were sequenced. The sequence data were analyzed by SAGE software and matched to GenBank and UniGene public databases. The sequence data were also compared with the choroid/RPE cDNA library of NEIBank. RESULTS: A total of 12 070 tags were sequenced; 3627 tags were unique. Of these 3627 tags, 2508 tags were encoded genes and 1119 tags were unknown tags in the UniGene database. The most frequently expressed tag was TCCCTATTAA, but the gene corresponding to this tag has not been identified yet. Other frequently expressed tags encoded a tissue inhibitor of matrix metalloproteinase 3, insulin-like growth factor binding protein-related protein 1, and transthyretin. These genes are notably different, with high expression frequencies when compared to the cDNA library of NEIBank. CONCLUSIONS: This gene expression profile of the normal human choroid/RPE tissue should provide further understanding of the biological function of the choroid and the pathogenesis of diseases in which the choroid and RPE play a role, such as choroidal neovascularization.

Aged↗

PubMed2006

Transcriptional profiling of Alzheimer blood mononuclear cells by microarray.

We evaluated pathomechanisms and systemic manifestations of Alzheimer disease (AD), an aging-related dementing neurodegenerative disorder, by expression profiling. Blood mononuclear cell (BMC) transcriptomes of sporadic AD subjects and aged-matched normal elderly controls (NEC) were compared using the human NIA microarray. Relative to the NEC samples, the Alzheimer BMC exhibited a significant decline in the expression of genes concerned with cytoskeletal maintenance, cellular trafficking, cellular stress response, redox homeostasis, transcription and DNA repair. We observed decreased expression of several genes which may impact amyloid-beta production and the processing of the microtubule-associated protein tau. The microarray results were validated by quantitative real time PCR and revealed gender differences in the levels of altered gene expression. Our findings attest to the systemic nature of gene dys-regulation in sporadic AD, implicate disruption of cytoskeletal integrity, DNA repair mechanisms and cellular defenses in this condition, and suggest novel pathways of beta-amyloid deposition in this disease. BMC are highly accessible and may reflect molecular events germane to the neuropathophysiology of AD.

Aged↗

PubMed2026

Whole-transcriptome-scale isoform-resolved spatial imaging of single cells in tissues.

Cell and tissue functions arise from complex interactions among numerous genes, and a systematic understanding of these functions requires isoform-resolved transcriptomic analysis of single cells with high spatial resolution. Here, we introduce an in situ RNA amplification method and its integration with multiplexed error-robust fluorescence in situ hybridization (MERFISH) to detect short RNA sequences and enable whole-transcriptome-scale, isoform-resolved spatial transcriptomics of individual cells in intact tissues. Using this approach, we imaged ∼33,000 distinct RNAs-including ∼23,000 genes and ∼10,000 isoforms-in the mouse brain. Our data enabled systematic analyses of region- and cell-type-specific gene programs and ligand-receptor-based cell-cell communications. These data further revealed rich spatial diversity and cell-type specificity in isoform usage across numerous genes, as well as brain structures particularly rich in isoform specificity. We anticipate broad application of this method for characterizing the molecular and cellular basis of tissue functions, unlocking previously inaccessible discoveries in cell and organismal biology.

Animals↗

PubMed2026

A High-Resolution Stereo-Seq Spatial Transcriptomic Resource for Adult Holstein Cattle Liver.

The bovine liver is a highly compartmentalized organ that plays essential roles in continuous gluconeogenesis and nitrogen recycling; however, its spatial molecular architecture has remained largely uncharacterized due to the limitations of traditional bulk and single-cell approaches. To address this gap, Spatial Enhanced Resolution Omics-sequencing (Stereo-seq) was utilized to generate a subcellular-resolution (500 nm) transcriptomic map of an adult Holstein cattle liver, and a refined reference-guided workflow was implemented to overcome standard annotation limitations in livestock. Raw sequencing data were processed using the Stereo-seq Analysis Workflow and analyzed with Stereopy, Seurat, SingleR, and reference-guided workflows. Spatial aggregation was evaluated at Bin20, Bin50, Bin100, Bin150, and Bin200. Increasing bin size increased molecular identifier counts and detected-gene complexity while progressively reducing spatial granularity. Bin50, corresponding to 50 × 50 DNA nanoballs and an approximate nominal footprint of 25 × 25 µm, was therefore selected as a practical intermediate aggregation level for the primary analyses. Quality-control assessment, Leiden clustering, UMAP visualization, reference-based cell-type annotation, cluster-marker analysis, and spatial mapping of canonical hepatic genes demonstrated preservation of biologically interpretable liver transcriptional organization. Raw sequencing data processed spatial matrices, annotated objects, and analysis code are publicly available to support reanalysis and computational benchmarking. In summary, we present a Stereo-seq spatial transcriptomic resource generated from liver tissue of an adult Holstein cow. This initial resource provides a valuable foundation for future studies of bovine liver biology, comparative genomics, and the spatial basis of livestock health and production traits.

Animals↗

PubMed2003

Molecular analysis of cancer using DNA and protein microarrays.

In conclusion, array-based technologies have emerged that contribute to profiling tissues at the genomic, transcriptomic and proteomic levels. Analytical tools are needed to mine the vast amount of data generated. Ultimately the molecular analysis of cancer at a genome and proteome scale will allow better classification of disease and tailored individualized therapy for individual patients.

Biotechnology↗

PubMed2026

Mining the sHSP20 (small heat-shock protein) gene family in finger millet (Eleusine coracana (L.) Gaertn.): structural, evolutionary and predicted abiotic-stress-responsive insights.

Small heat-shock proteins (sHSPs, the HSP20 family) are ATP-independent molecular chaperones that hold partially unfolded substrates and protect the proteome during heat and other abiotic stresses; every member is defined by a conserved α-crystallin domain (ACD). Finger millet (Eleusine coracana) is a climate-resilient, calcium-rich allotetraploid cereal of the semi-arid tropics whose HSP20 repertoire had not been catalogued. The present study is an entirely computational (in silico) analysis of the chromosome-scale reference genome of finger millet (NCBI GenBank assembly GCA_032690845.1, cultivar KNE 796-S). Mining the predicted proteome with the ACD profile (Pfam PF00011) and confirming every candidate by NCBI CD-search recovered 76 non-redundant ACD-bearing HSP20 genes (EcHSP20-1-EcHSP20-76). Based on phylogeny and TargetP-predicted localization, the members were classified into ten subfamilies: seven cytosolic/nuclear classes (C-I to C-VII, 60 members) together with chloroplastic (11), mitochondrial (3) and endoplasmic-reticulum (2) groups. The proteins ranged from 110 to 355 amino acids (12.1-39.2 kDa) with theoretical pI of 4.85-9.69. The 76 loci were distributed over 14 of the 18 chromosomes and were conspicuously absent from chromosomes 8 A, 8B, 9 A and 9B, with pronounced clustering on chromosomes 1, 2, 3 and 6. Duplication analysis detected 149 paralogous pairs (49 homoeologous, 80 segmental/dispersed and 18 tandem); 147 of 148 pairs for which substitution rates could be calculated returned Ka/Ks < 1 (mean 0.20), indicating strong purifying selection consistent with retention after whole-genome/allopolyploid duplication. Promoter analysis (PlantCARE) revealed enrichment of abscisic-acid-responsive (ABRE), MYB/MYC drought-related, STRE, DRE, low-temperature (LTR) and methyl-jasmonate/salicylic-acid elements, whereas canonical heat-shock elements (HSE) were not recovered. Expression profiling against a public drought transcriptome (SRP081350) showed that about half of the genes (39 of 76) are transcribed in leaf tissue, the expressed fraction being dominated by the cytosolic class C-I. This first finger-millet HSP20 catalogue provides a verified, reproducible framework and nominates computationally predicted candidate genes for future functional work on thermotolerance in cereals.

Allotetraploid↗

PubMed2004

Adaptation of enzymes to temperature: searching for basic "strategies".

The pervasive influence of temperature on biological systems necessitates a suite of temperature--compensatory adaptations that span all levels of biological organization--from behavior to fine-scale molecular structure. Beginning about 50 years ago, physiological studies conducted with whole organisms or isolated tissues, by such pioneers of comparative thermal physiology as V.Ya. Alexandrov, T.H. Bullock, F.E.J. Fry, H. Precht, C.L. Prosser, and P.F. Scholander, began to document in detail the abilities of ectothermic animals to sustain relatively similar rates of metabolic activity at widely different temperatures of adaptation or acclimation. These studies naturally led to investigation of the roles played by enzymatic proteins in metabolic temperature compensation. Peter Hochachka's laboratory became an epicenter of this new focus in comparative physiology. The studies of the enzyme lactate dehydrogenase (LDH) that he initiated as a PhD student at Duke University in the mid-1960s and continued for several years at the University of British Columbia laid much of the foundation for subsequent studies of protein adaptation to temperature. Studies of orthologs of LDH have revealed the importance of conserving kinetic properties (catalytic rate constants (kcat) and Michaelis-Menten constants (Km) and structural stability during adaptation to temperature, and recently have identified the types of amino acid substitutions causing this adaptive variation. The roles of pH and low-molecular-mass organic solutes (osmolytes) in conserving the functional and structural properties of enzymes also have been elucidated using LDH. These studies, begun in Peter Hochachka's laboratory almost 40 years ago, have been instrumental in the development of a conceptual framework for the study of biochemical adaptation, a field whose origin can be traced largely to his creative influences. This framework emphasizes the complementary roles of three "strategies" of adaptation: (1) changes in amino acid sequence that cause adaptive variation in the kinetic properties and stabilities of proteins, (2) shifts in concentrations of proteins, which are mediated through changes in gene expression and protein turnover; and (3) changes in the milieu in which proteins function, which conserve the intrinsic properties of proteins established by their primary structure and modulate protein activity in response to physiological needs. This theoretical framework has helped guide research in adaptational biochemistry for many years and now stands poised to play a critical role in the post-genomic era, as physiologists grapple with the challenge of integrating the wealth of new data on gene sequences (genome), gene expression (transcriptome and proteome), and metabolic profiles (metabolome) into a realistic physiological context that takes into account the evolutionary histories and environmental relationships of species.

Adaptation, Physiological↗

PubMed2006

Layered expression scanning: multiplex molecular analysis of diverse life science platforms.

With the advent of the genomic era, there is an increasing use of high-throughput techniques to generate transcriptome- and proteome-based profiles of biological specimens. Each of these methodologies offers a unique window into the inner workings of cell and tissue samples. Often, these studies generate large data sets and provide investigators with a substantial number of candidate dysregulated genes and pathways. Follow-up studies are then undertaken to independently validate the original findings and to extend the study to additional samples or more quantitative measurements. Although there are several methods available for these validation efforts, they are often tedious and laborious to perform; thus, additional tools that enable this task are needed. One such approach is layered expression scanning (LES), a new technique developed via a cooperative research and development agreement (CRADA) between the National Cancer Institute and 20/20 GeneSystems, Inc. The technique is based on the movement of biomolecules from a two-dimensional life science platform (histological tissue section, electrophoresis gel, multi-well plate, etc.) through a set of analysis membranes while maintaining the original distribution pattern of the molecules. Each membrane measures one analyte and the data are then mapped back to the original specimen, permitting each component of the life science platform to be studied in detail. LES can be configured in several different ways depending on the goals of the study. In this review, we summarize the use of the LES technique for a variety of biological applications.

Membranes, Artificial↗

PubMed2006

Immune cell transcriptome datasets reveal novel leukocyte subset-specific genes and genes associated with allergic processes.

BACKGROUND: The precise function of various resting and activated leukocyte subsets remains unclear. For instance, mast cells, basophils, and eosinophils play important roles in allergic inflammation but also participate in other immunologic responses. One strategy to understand leukocyte subset function is to define the expression and function of subset-restricted molecules. OBJECTIVE: To use a microarray dataset and bioinformatics strategies to identify novel leukocyte markers as well as genes associated with allergic or innate responses. METHODS: By using Affymetrix microarrays, we generated an immune transcriptome dataset composed of gene profiles from all of the major leukocyte subsets, including rare enigmatic subsets such as mast cells, basophils, and plasma cells. We also assessed whether analysis of genes expressed commonly by certain groups of leukocytes, such as allergic leukocytes, might identify genes associated with particular responses. RESULTS: Transcripts highly restricted to a single leukocyte subset were readily identified (>2000 subset-specific transcripts), many of which have not been associated previously with leukocyte functions. Transcripts expressed exclusively by allergy-related leukocytes revealed well known as well as novel molecules, many of which presumably contribute to allergic responses. Likewise, Nearest Neighbor Analysis of genes coexpressed with Toll-like receptors identified genes of potential relevance for innate immunity. CONCLUSION: Gene profiles from all of the major human leukocyte subsets provide a powerful means to identify genes associated with single leukocyte subsets, or different types of immune response. CLINICAL IMPLICATIONS: A comprehensive dataset of gene expression profiles of human leukocytes should provide new targets or biomarkers for human inflammatory diseases.

Gene Expression Profiling↗

PubMed2005

Gene expression perturbation in vitro--a growing case for three-dimensional (3D) culture systems.

Cells grown in vitro are dramatically perturbed by their new microenvironment. Analyses of genome-wide gene expression levels offer a first glance at which genes and pathways are affected in cell lines as compared to their tissues of origins. We have summarized available gene expression data and review how cell lines adapt to in vitro environments, to what degree they express markers of their tissues of origins and discuss how cells grown in three-dimensional (3D) cultures may have more physiological interactions with neighbouring cells and extracellular matrix. We will also discuss the interplay between malignant cells and stroma present in tumours but lacking in cell lines and how these differences might affect gene expression comparisons of cell lines to tumours. A model simulating impact of stromal cells on gene expression profiles is presented. Understanding the transcriptomes of cells grown in 2D and 3D cultures and how they compare to those of in vivo cells are important for improving cell line model systems and for the reconstituting of tissues in vitro.

Cell Adhesion↗

PubMed2026

A ribozyme ligase that requires a 3' terminal phosphate on its RNA substrate.

Ribozymes likely played essential roles in catalyzing metabolic processes and facilitating genome replication in primordial RNA-based life. In vitro evolution has allowed us to expand the biochemical capabilities of RNA, especially new ribozyme chemistries. Here, we report the serendipitous discovery of ribozyme ligases that catalyze the attack of the 2'-hydroxyl group of an RNA substrate on its own 5'-triphosphate group, but only when the substrate possesses a 3'-phosphate vicinal to its nucleophilic 2'-hydroxyl group. The ligases' requirement for a 3'-phosphate group on its substrate resembles enzymatic mechanisms found in protein-based RNA repair pathways. We propose that ribozyme-catalyzed ligation of 3'-phosphorylated RNA could have provided pathways for RNA repair in primordial cells. We demonstrate that these ribozymes ligate specifically to 3'-phosphorylated RNA present in a heterogeneous mixture of cellular RNAs. We further show that these ribozymes can capture cleaved RNAs with 3'-phosphate and 2'-3'-cyclic phosphate termini, enabling us to selectively amplify the captured RNAs. These results demonstrate their potential utility as enrichment reagents for profiling RNA cleavage products in transcriptomics studies. Our findings not only report a new catalytic reactivity in RNA but also provide insights into ribozyme evolution, primordial RNA repair, and potential applications in RNA sequencing.

RNA, Catalytic↗

PubMed2026

Mapping convergent regulators of melanoma drug resistance by PerturbFate.

High-throughput genomic studies have uncovered associations between diverse genetic alterations and disease phenotypes. However, elucidating how perturbations in functionally disparate genes give rise to convergent cellular states remains challenging. Here we present PerturbFate, a high-throughput, cost-effective, combinatorial-indexing single-cell platform that enables systematic interrogation of massively parallel CRISPR interference1 perturbations across the full spectrum of gene regulation, from chromatin remodelling and nascent transcription to steady-state transcriptomic phenotypes. Using PerturbFate, we profiled more than 300,000 cultured melanoma cells to characterize multimodal phenotypic and gene regulatory responses to perturbations in more than 140 vemurafenib resistance-associated genes. We uncovered a shared dedifferentiated cell state marked by convergent cooperative transcription factor activities across diverse genetic perturbations. We further dissected phenotypic responses to perturbations in Mediator complex components, linking module-specific biochemical properties to convergent transcriptional activations. We identified common regulatory nodes that drive similar phenotypic outcomes across distinct genetic perturbations. We also delineated how perturbations in functionally unrelated genes reshape cell state. Thus, PerturbFate establishes a versatile platform for identifying key molecular regulators by anchoring multimodal regulatory dynamics to disease-relevant phenotypes.

Humans↗